The widespread deposition of fibrin within joints is one of the most striking features of rheumatoid arthritis. Fibrin accumulates on synovial and cartilage surfaces and is a key component of particulate "rice" bodies within the synovial fluid. Based on studies in other inflammatory contexts, there is considerable evidence that the local formation of fibrin(ogen) matrices and/or fibrin degradation products are critical to the infiltration and/or function of inflammatory cells at sites of tissue damage. In this research proposal, we wish to directly test the hypothesis that the local deposition and dissolution of fibrin(ogen) within synovial tissue is crucial to the inflammatory processes that lead to the synovial remodeling, pannus formation, neovascularization, cartilage destruction and bone erosion associated with arthritis. We plan to determine the impact of systemic deficiencies in fibrinogen,plasminogen activator, and plasminogen on joint inflammation and degeneration using two mouse models of rheumatoid arthritis with distinct immunological features: i) "spontaneous" arthritis in transgenic mice expressing the inflammatory cytokine, TNFalpha, and ii) collagen-induced arthritis (CIA). Our working hypothesis is that fibrin(ogen) deficiency will significantly delay, if not eliminate, inflammatory infiltrates, synovial thickening, pannus formation, and cartilage and bone destruction. By contrast, deficits in plasminogen activation system components will increase fibrin deposition within arthritic joints worsen joint inflammation, and promote tissue destruction.